X-8798441-G-A

Variant names:

• chrX-8798441-G-A
• rs1260714082
• NM_174951.3:c.259C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174951.3(FAM9A):​c.259C>T​(p.Pro87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,097,775 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: FAM9A NM_174951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.583

Genes affected

FAM9A (HGNC:18403): (family with sequence similarity 9 member A) This gene is a member of a gene family which arose through duplication on the X chromosome. The encoded protein may be a nuclear protein that is localized to the nucleolus, and has some similarity to a synaptonemal complex protein. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15064475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3	c.259C>T	p.Pro87Ser	missense_variant	Exon 4 of 10	ENST00000381003.7	NP_777611.1
FAM9A	NM_001171186.1	c.259C>T	p.Pro87Ser	missense_variant	Exon 4 of 10		NP_001164657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9A	ENST00000381003.7	c.259C>T	p.Pro87Ser	missense_variant	Exon 4 of 10	1	NM_174951.3	ENSP00000370391.3
FAM9A	ENST00000543214.1	c.259C>T	p.Pro87Ser	missense_variant	Exon 4 of 10	1		ENSP00000440163.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1097775 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363147

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259C>T (p.P87S) alteration is located in exon 4 (coding exon 3) of the FAM9A gene. This alteration results from a C to T substitution at nucleotide position 259, causing the proline (P) at amino acid position 87 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.7
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T;T
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.72	T;.
M_CAP	Benign	0.00053	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L;L
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.028
Sift	Benign	0.076	T;T
Sift4G	Benign	0.38	T;T
Polyphen		1.0	D;D
Vest4		0.077
MutPred		0.22		Gain of phosphorylation at P87 (P = 0.0071);Gain of phosphorylation at P87 (P = 0.0071);
MVP		0.11
MPC		0.33
ClinPred		0.37	T
GERP RS		0.74
Varity_R		0.092
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1260714082; hg19: chrX-8766482; COSMIC: COSV105318383;